Postzygotic Mutation Research Articles

33701 Porokeratotic eccrine ostial and dermal duct nevus caused by a second-hit postzygotic GJB2 mutation

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare type of epidermal nevus involving the eccrine acrosyringia. It typically presents as asymptomatic linear keratotic papules and plaques along the lines of Blaschko which predominantly affects the extremities, and the disease has recently been linked to GJB2 somatic mutations. To the best of our knowledge, only four mutations have been documented from GJB2 in pure PEODDN cases. Herein, we reported an 18-year-old female who presented with a hyperkeratotic plaque on the dorsal side of the proximal interphalangeal joint of her right ring finger as well as multiple small linear hyperkeratotic papules distributed over the lateral side of her her right index, middle and ring fingers noted since her birth. Histopathologic study revealed prominent parakeratotic cornoid lamella-like tiers at the opening of eccrine secretory ducts. Sanger sequencing focusing on the GJB2 gene revealed a germline heterozygous missense mutation, c.608T>C (p.Ile203Thr) in the blood and the epidermal tissue of the affected skin. Whole exome sequencing (WES) on the genomic DNA extracted from the lesional epidermis identified another second-hit postzygotic somatic reported missense mutation, c.263C>A (p.Ala88Glu) with low mosaic percentage of around 4% and reflecting the dilutional effect in biopsy of whole tissue and limit of detection by Sanger sequencing. In conclusion, this study presents a case of PEODDN with a complete genetic study identifying a germline mutation and a second-hit postzygotic somatic mutation; our findings strengthen the importance of second- hit somatic mutation in GJB2 as an etiology in PEODDN.

Inflammatory linear verrucous epidermal nevus (ILVEN) encompasses a spectrum of inflammatory mosaic disorders.

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported. To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN. We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified. Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations. ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.

Evidence of neural crest cell origin of a DICER1 mutant CNS sarcoma in a child with DICER1 syndrome and NRAS-mutant neurocutaneous melanosis.

Evidence of neural crest cell origin of a DICER1 mutant CNS sarcoma in a child with DICER1 syndrome and NRAS-mutant neurocutaneous melanosis.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

QS11. Proteasome Inhibitors Effectively Inhibit Venous and Lymphatic Malformations

Purpose: Venous and lymphatic malformations (VMs and LMs) carry postzygotic somatic mutations in malformation endothelial cells (VMECs, LMECs), leading to PI3K/AKT/mTOR hyperactivation.Off-label treatment with sirolimus, an mTOR inhibitor, and alpelisib, a PI3K inhibitor, has been effective, confirming the validity of a pharmacological approach in the treatment of VMs and LMs. However, treatment response is incomplete. We hypothesized that a high-throughput screen (HTPS) against VMECs and LMECs carrying PIK3CA mutations would identify novel candidate drugs to be used in the treatment of VMs and LMs. Methods: FDA-approved/in-clinical-trial drugs at 1uM concentration, and percent viability relative to vehicle-treated controls was determined at 48 hours. A dose response viability assay was performed to compare effective inhibitors to sirolimus and alpelisib. In a xenograft mouse model, VMECs (n=2) and LMECs (n=2) carrying PIK3CA variants were resuspended in Matrigel, which were subcutaneously implanted into the flanks of nude mice. Malformations were allowed to develop for either one week (VMs) or two weeks (LMs) before beginning randomized treatment with either oprozomib (a proteasome inhibitor) or a vehicle. Oprozomib was administered by mouth at 30mg/kg 2x per week for 4 weeks. Implants were harvested and analyzed histologically and by immunofluorescence, and relative vascular areas to total implant areas were measured. Statistical analysis was performed with one-way ANOVA with posthoc Tukey’s HSD as well as student’s t-test. Results: HTPS identified three proteasome inhibitors (PIs) that significantly suppressed VMEC and LMEC viability when compared to sirolimus and alpelisib: carfilzomib, delanzomib, and ixazomib (p<0.0001, ANOVA). In a dose response viability assay, all 6 PIs significantly inhibited VMEC and LMEC at clinically relevant doses (p<0.005, student’s t-test. Oprozomib was well-tolerated by mice in the xenograft model and effectively inhibited VM and LM development. When oprozomib-treated implants were compared to controls, LM channel sizes were significantly decreased (p<0.02), and relative vascular area of VM implants were also significantly decreased (p<0.007, student’s t-test). Conclusion: We identified a novel class of drugs, proteasome inhibitors, that significantly inhibited VMEC and LMEC viability in vitro and in vivo. These PIs had superior efficacy in VMEC and LMEC inhibition relative to sirolimus and alpelisib. These data demonstrate that proteasome inhibitors may be efficacious in VM and LM treatment. Additional studies are needed to further understand mechanisms of PI efficacy.

An update on Becker's nevus: Pathogenesis and treatment.

Becker's nevus (BN) manifests as a hyperpigmented, sometimes hypertrichotic plaque/patch over the chest and shoulder, and it is in the category of benign cutaneous hamartomas. BN has elongation and fusion of the rete ridge, keratotic plugging, sebaceous hyperplasia, smooth muscle hyperplasia, and hyperpigmentation of the basal/suprabasal layer histologically. This article highlights all issues involved in pathogenesis and treatment options of BN. According to current research, postzygotic ACTB mutations induce BN and Becker's nevus syndrome (BNS). Although several therapy strategies were utilized to treat the pigmentary and hypertrichotic aspects of BN, no definitive standard treatment was identified to far, and further research is needed to better educate BN care.

Early embryonic mutations reveal dynamics of somatic and germ cell lineages in mice.

De novo mutations accumulate with zygotic cell divisions. However, the occurrence of these mutations and the way they are inherited by somatic cells and germ cells remain unclear. Here, we present a novel method to reconstruct cell lineages. We identified mosaic mutations in mice using deep whole-genome sequencing and reconstructed embryonic cell lineages based on the variant allele frequencies of the mutations. The reconstructed trees were confirmed using nuclear transfer experiments and the genotyping of approximately 50 offspring of each tree. The most detailed tree had 32 terminal nodes and showed cell divisions from the fertilized egg to germ cell– and somatic cell–specific lineages, indicating at least five independent cell lineages that would be selected as founders of the primordial germ cells. The contributions of each lineage to germ cells and offspring varied widely. At the emergence of the germ cell–specific lineages, 10–15 embryonic mutations had accumulated, suggesting that the pregastrulation mutation rate is 1.0 mutation per mitosis. Subsequent mutation rates were 0.7 for germ cells and 13.2 for tail fibroblasts. Our results show a new framework to assess embryonic lineages; further, we suggest an evolutionary strategy for preserving heterogeneity owing to postzygotic mutations in offspring.

Single-molecule, quantitative detection of low-abundance somatic mutations by high-throughput sequencing.

Postzygotic somatic mutations have been found associated with human disease, including diseases other than cancer. Most information on somatic mutations has come from studying clonally amplified mutant cells, based on a growth advantage or genetic drift. However, almost all somatic mutations are unique for each cell, and the quantitative analysis of these low-abundance mutations in normal tissues remains a major challenge in biology. Here, we introduce single-molecule mutation sequencing (SMM-seq), a novel approach for quantitative identification of point mutations in normal cells and tissues.

Cutis marmorata telangiectatica congenita being caused by postzygotic GNA11 mutations

Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of “nevus vascularis mixtus”. Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype.

Familial long-read sequencing increases yield of de novo mutations

Studies of de novo mutation (DNM) have typically excluded some of the most repetitive and complex regions of the genome because these regions cannot be unambiguously mapped with short-read sequencing data. To better understand the genome-wide pattern of DNM, we generated long-read sequence data from an autism parent-child quad with an affected female where no pathogenic variant had been discovered in short-read Illumina sequence data. We deeply sequenced all four individuals by using three sequencing platforms (Illumina, Oxford Nanopore, and Pacific Biosciences) and three complementary technologies (Strand-seq, optical mapping, and 10X Genomics). Using long-read sequencing, we initially discovered and validated 171 DNMs across two children-a 20% increase in the number of de novo single-nucleotide variants (SNVs) and indels when compared to short-read callsets. The number of DNMs further increased by 5% when considering a more complete human reference (T2T-CHM13) because of the recovery of events in regions absent from GRCh38 (e.g., three DNMs in heterochromatic satellites). In total, we validated 195 de novo germline mutations and 23 potential post-zygotic mosaic mutations across both children; the overall true substitution rate based on this integrated callset is at least 1.41× 10-8 substitutions per nucleotide per generation. We also identified six de novo insertions and deletions in tandem repeats, two of which represent structural variants. We demonstrate that long-read sequencing and assembly, especially when combined with a more complete reference genome, increases the number of DNMs by >25% compared to previous studies, providing a more complete catalog of DNM compared to short-read data alone.

McCune–Albright syndrome: description of three clinical cases, features of diagnostics and treatment

McCune Albright syndrome (MAS) is a rare disorder caused by a sporadic postzygotic mutation in the GNAS gene, which encodes the alpha subunit of the Gs signaling protein.Permanent activation of the Gs protein leads to uncontrolled production of intracellular cAMP, and autonomic hyperfunction of target organs. Estimated prevalence of the disease – 1\100000 to 1\1000000. For the first time, MAS syndrome was described in 1936 as a triad of symptoms – fibrous dysplasia of bones (FD), spots on the skin of the color of «coffee with milk» and premature sexual development. However, it is now known, that the phenotype of the disease is much more complex. This is primarily due to the mosaic type of mutation in the GNAS gene, which determines a wide range of clinical manifestations, and presents certain difficulties in the diagnosis of this syndrome. Various endocrinopathies can be manifestations of MAS like an acromegaly, a hyperthyroidism, Cushing’s syndrome, hypophospatemic osteomalacia as well as damage to other organs and systems, namely the pathology of the gastrointestinal tract, hepato-biliary cardiovascular systems. This article presents three late diagnosed clinical cases of MAS in patients with coffee-milk spots and FD, multinodular goiter; in two cases in combination with acromegaly. We have demonstrated the possibilities of drug therapy for acromegaly in MAS, as well as the experience of using bisphosphonate for the treatment of FD.The knowledge of clinical manifestations of the MAS, early diagnostics and possibilities of drug therapy in the management of these patients have the important prognostic value for improving the quality of patient’s life.

Activating PIK3CA postzygotic mutations in segmental overgrowth of muscles with bone involvement in the body extremities.

Segmental overgrowth of the skeletal muscles with bone involvement in body extremities, predominantly affecting the upper limb, is an extremely rare condition with only 40-50 affected children described clinically. The molecular pathogenesis of this disorder remains largely unclear except for the identification of a somatic PIK3CA mutation in each of the six patients genetically tested, all restricted to upper limbs in the literature. This study aimed to further characterize the molecular defects for patients affected with segmental overgrowth of the skeletal muscles by analyzing a 9-gene panel selected from the PI3K/AKT/mTOR pathway and genes associated with other related conditions. Nineteen unrelated patients were chosen for this study, comprising ten upper limb (nine unilateral and one bilateral) and nine lower limb (eight unilateral and one bilateral) cases with variable bone involvement. In each case, an activating PIK3CA mutation (p.E110del, p.N345K, p.E542K, p.E545K, p.H1047R, or p.H1047L) was identified in the affected muscle tissue with variant allele frequencies ranging from 13.88 to 30.43%, while no mutation was detected in the paired peripheral blood sample, indicating somatic mosaicism. All detected mutations were limited to PIK3CA and were previously reported in other overgrowth syndromes currently categorized under the PIK3CA-Related Overgrowth Spectrum (PROS). Our study provides strong molecular evidence that isolated segmental overgrowth of the skeletal muscle with bone involvement is a subtype of PROS. Our findings expand the PROS clinical presentations with a newly molecularly classified condition and can provide guidance in clinical and molecular diagnosis and treatment for patients with this condition.

Mutational Landscape of Autism Spectrum Disorder Brain Tissue.

Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes. Although quantification did not reveal enrichment for post-zygotic mutations compared with the controls (n = 15), a small number of pathogenic, potentially ASD-implicated mutations were identified, notably in TRAK1 and CLSTN3. Furthermore, germline mutations were identified in the same tissue samples in several key ASD genes, including PTEN, SC1A, CDH13, and CACNA1C. The establishment of tissue resources that are available to the scientific community will facilitate the discovery of new mutations for ASD and other neurodevelopmental disorders.

Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts

BackgroundPrimary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and...

ACTB Mutations Analysis and Genotype-Phenotype Correlation in Becker's Nevus.

Becker’s nevus (BN) is a cutaneous hamartoma which is characterized by circumscribed hyperpigmentation with hypertrichosis. Recent studies have revealed that BN patients harbored postzygotic ACTB mutations, which were restricted to arrector pili muscle lineage. We screened for ACTB mutations in 20 Chinese patients with BN and found that recurrent mutations (c.C439A or c.C439T) in ACTB were detected in the majority of BN patients. However, more than 20% of the patients were negative for ACTB mutations, suggesting a possible genetic heterogeneity in Becker’s nevus. Interestingly, these mutations were also detected in dermal tissues outside the arrector pili muscle. We further performed genotype–phenotype correlation analysis, which revealed that lesions above the waistline, including the trunk above the anterior superior spine level, upper limbs and face, or covering more than 1% BSA were more likely to be positive for ACTB mutations. Altogether, our results provide further evidence of postzygotic ACTB mutations in BN patients and suggest a possible genotype–phenotype correlation of BN.

Mosaicism in clinical genetics.

Genetic mosaicism is the state in which there are two or more different sets of cells in a single individual because of one or more postzygotic mutations, and its importance in clinical genetics has long been recognized (Hall, Am J Hum Genet 43: 355 [1988]). In this Perspective, a paper in this special issue on mosaicism from Cook et al. (Cold Spring Harb Mol Case Studies 7: a006125 [2021]) is discussed.

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA.

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K–RAS–MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170–173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048–1054.e1–5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496–1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287–295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet–Dechaume–Blanc syndrome, and Wyburn–Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5–17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245–258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103–2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA. We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

Sirolimus Leads to Rapid Improvement in Fibroadipose Vascular Anomalies

Purpose: Fibroadipose vascular anomaly (FAVA) is a complex vascular anomaly associated with postzygotic somatic PIK3CA mutations. FAVAs can cause significant pain, swelling, and musculoskeletal dysfunction. Treatment options are limited. Sirolimus is a well-tolerated and effective treatment for patients with FAVA. We report our experience of using sirolimus to treat 11 children with FAVAs. Methods: We conducted a retrospective review of all patients with FAVA treated with sirolimus in our institution. Results: Fourteen patients (10 females) were referred for sirolimus therapy for FAVA. Eleven patients were initiated on sirolimus at a mean age of 14 years (range: 9–17.9 years) and were then treated for a mean of 19 months (range: 1–46 months). Five had previously undergone sclerotherapy without benefit. Sirolimus was initiated at a dose of either 2.5 mg/m2 once daily or 0.8 mg/m2 twice daily. Doses were titrated to maintain sirolimus trough levels of 5–15 ng/L. Goals of treatment were improvement in pain and musculoskeletal dysfunction. All 11 patients reported reduced pain; 7 reporting this within 3 weeks of starting sirolimus. This allowed for discontinuation of analgesia. Function improved significantly in 9 of 11, leading to resumption of sports or work participation. Sirolimus side effects were similar to prior reports, most commonly mouth sores, mildly elevated lipids and acne. There was no grade III/IV toxicity. Conclusion: Sirolimus is a well-tolerated and effective treatment for patients with FAVA. Initial symptom improvement is rapid, with significantly reduced pain and improved function. We believe that sirolimus should be considered for all patients with FAVA as a first-line therapy before surgical/interventional approaches.

Verrucous epidermal nevus: diagnostic difficulties.

Along Blachko’s lines are distributed diseases with Mendelian inheritance such as incontinentia pigmenti, polygenic hereditary diseases such as psoriasis or atopic dermatitis (3), nevi such as verrucous epidermal nevus (VEN) and its inflammatory variant (1), and acquired diseases such as lichen striatus (LS). All these diseases share a condition of mosaicism, that is, they presuppose the existence of a gene mutation, often post-zygotic, that gives rise to a clone of cells different from all the others. The type of mutated gene is responsible for the different morphology of these diseases, but the distribution on the skin of the mutated clone is always the same; therefore, it does not depend on the gene, but on the time in which the mutation occurred and on the stereotyped movements of the migrations that skin cells undergo during fetal life. If the nevus is very extensive and therefore secondary to an early mutation, other organs may be involved such as the nervous system, the eye, the skeletal system, as happening in epidermal nevus syndrome (4) or even some gonadal cells with the risk that the mutation is transmitted to the zygote of the offspring thus giving rise to a generalized inherited disease (5). VEN is usually present at birth; when it is localized in hidden locations or when it initially manifests with just hyperpigmented lesions it may become evident later. However, it is exceptional that it manifests itself at 8 years as in the present case. Its earliness and its morphology are able in most cases to easily differentiate it from an acquired inflammatory condition such as LS. LS is a self-healing inflammatory skin disease, usually asymptomatic, which affects the first years of age, usually between 5 and 15 years, and is distributed linearly along Blaschko’s lines, suggesting that on the line in which it occurs there is a clone of mutated cells as a result of a post-zygotic mutation: this mutation would give the cells involved a particular susceptibility towards an exogenous agent that, upon its arrival, would cause the transient inflammatory reaction (2). There are various hypotheses on the pathogenetic mechanisms that lead to the inflammatory reaction and its spontaneous regression. The present case has posed problems of differential diagnosis between VEN and LS. The histological findings were not able to eliminate the clinical doubt, indeed they added another possible differential diagnosis, i.e. inflammatory linear verrucous epidermal nevus. The latter diagnosis was discarded due to the lack of itching and obvious clinical signs of inflammation. Only prolonged clinical observation over time resolved the diagnostic doubt thanks to the persistence of the lesions and the greater evidence of papillomatous and warty structures.

Cutaneous mosaicism: Special considerations for women.

Genetic mosaicism results from postzygotic mutations during embryogenesis. Cells harboring pathogenic mutations distribute throughout the developing embryo and can cause clinical disease in the tissues they populate. Cutaneous mosaicism is readily visualized since affected tissue often follows predetermined patterns, such as lines of Blaschko. Due to its clinical accessibility, cutaneous mosaicism is well suited for genetic analysis. An individual's unaffected tissue can be used as an intrapatient genetic control, a technique that has yielded insight into the genetic etiologies of many disorders, several of which bear mutations in genes that would otherwise be embryonic-lethal. Particular mosaic diseases can also disproportionally impact women. Two such diseases, incontinentia pigmenti (IP) and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome, arise from mutations on the X chromosome. Both diseases result in fetal demise in males in most cases, thus making the two diseases largely specific to women. Women with McCune–Albright Syndrome, caused by somatic mutations in GNAS, often experience precocious puberty and infertility as a result of uncontrolled cAMP regulation in affected tissue. Women with cutaneous mosaicism carry a risk of transmission to offspring when gonosomal mosaicism is present, yet cutaneous disease burden does not correlate with germline transmission risk. Cutaneous mosaic disease represents a biologically unique set of disorders that can warrant special clinical attention in women.